Abstract 6026: Iron metabolism underlies the activation of cancer associated fibroblasts

Abstract Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among major cancers with a 5-year survival rate of 13%. This malignant disease is characterized by a dense, fibrotic stroma primarily driven by cancer-associated fibroblasts (CAFs). However, little is known about the molecular mechanism underlying the activation of CAFs. Our analysis of ATAC-seq conducted on in vitro myofibroblasts/inflammatory CAF (myCAFs/iCAFs) models suggest that a distinct landscape of chromatin accessibility underlies the activation of pancreatic stellate cells into both myCAFs and iCAFs. Here, we show that pharmacologic inhibition of the p300/CBP histone acetyltransferase complex with A485 suppresses activated CAF morphology, CAF transcriptional signatures, as well as the growth of tumor organoids in co-culture systems. Interestingly, RNA-seq analysis revealed an upregulation of heme metabolism that coincides with A485 treatment for both myCAFs and iCAFs, suggesting the potential dependency of CAF activation on iron metabolism. Both iCAFs and myCAFs also showed significantly reduced viability and CAF marker expression upon iron chelation compared with quiescent PSCs, and iron supplementation rescued this phenotype. Together, these findings suggest a link between epigenetics and iron metabolism in the context of CAF activation. Targeting the iron metabolic pathway for CAFs in PDAC may therefore serve as a promising strategy to reduce stromal remodeling and improve therapeutic interventions. Citation Format: Kedi Huang, Minh Duc Pham, Chang-il Hwang. Iron metabolism underlies the activation of cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6026.